Despite the markedly increased risk of stroke, nearly 50% of older adults with non-valvular atrial fibrillation (AF) did not follow clinical guidelines to receive anticoagulation therapy. Alzheimer?s disease and Alzheimer?s disease related dementia (AD/ADRD), and other features highly associated with AD/ADRD, including falls, and difficulty in maintaining good anticoagulation quality when receiving warfarin are among the major barriers of oral anticoagulant (OAC) prescribing. These factors also complicate the decisions regarding the optimal choice among specific OACs and appropriateness of switching a warfarin user to receive one of the direct oral anticoagulants (DOAC), which have more predictable pharmacokinetic profiles and cause less intracranial hemorrhage than does warfarin. Despite the seemingly abundant data from randomized controlled trials (RCTs) and routine-care settings, there was very little data evaluating the effects of OACs specifically in patients with AD/ADRD and its associated high-risk features, leaving large numbers of AF patients with AD/ADRD unanticoagulated without clear guidance. Because RCTs are unlikely to recruit and retain older adults with AD/ADRD that is representative of the patients in routine care, we aim to address these critical knowledge gaps with a combined dataset incorporating rich clinical information from electronic health records and longitudinal claims data covering >3 millions nationally representative Medicare beneficiaries aged 65 and above with non-valvular AF from 2011-2018, using state-of-the-art methodologies. Our specific aims include: 1) Determine comparative effectiveness and safety of use vs. non-use of oral anticoagulants in patients aged 65 and above with non-valvular AF and AD/ADRD (stratified by a validated activities of daily living [ADL] score and use of dementia medications), and/or high-risk features associated with AD/ADRD, including poor predicted anticoagulation quality and high risk of falls assessed by a validated algorithms; 2): Determine comparative effectiveness and safety of warfarin vs. specific DOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) in patients aged 65 and above with non-valvular AF and AD/ADRD, and/or high-risk features associated with AD/ADRD; 3) Determine comparative effectiveness and safety of switching to a DOAC vs. continuing warfarin in chronic users of warfarin aged 65 or older with non-valvular AF and AD/ADRD, and/or high-risk features associated with AD/ADRD. Successful accomplishment of this study will provide data to help clinicians estimate accurately the net clinical benefit of anticoagulation therapy in the vulnerable older adults with AD/ADRD and non-valvular AF, which will 1) support optimal use and b) avoid unnecessary withholding of an OAC. Importantly, this research will also produce a novel, generalizable approach to evaluate treatment effect heterogeneity of drug therapy by important clinical factors using both electronic health records and health insurance claims data with optimal validity and estimation precision.